Normally functioning b-Raf is a kinase which is involved in the relay of signals from the cell membrane to the nucleus and is active only when it is needed to relay such signals. Mutant b-Raf containing a V600E mutation, however, is constantly active and thus plays a role in tumor development. Such mutant b-Raf has been implicated in various tumors, for example, colorectal cancer, melanoma, and thyroid cancer.
Propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (hereafter also referred to as “Compound I”) is a b-raf kinase inhibitor that specifically targets mutant b-Raf containing the V600E mutation. This compound is described in WO 2007/002325. Accordingly, such an inhibitor is used in the inhibition of tumors, particularly solid tumors, for example, colorectal cancer, melanoma, and thyroid cancer, which comprise b-Raf having the V600E mutation.
Interferons (IFNs) are naturally occurring proteins that have antiviral, antiproliferative, and immunoregulatory activity. The IFNα family represents the predominant class of IFNs produced by stimulated peripheral blood leukocytes and lymphoblastoid and myeloblastoid cell lines. Interferons downregulate the expression of bFGF. These drugs can be self administered by patients via subcutaneous injection with resultant good pharmacokinetics. For the purpose of the present specification, the term “interferon” shall refer also to modified interferons and/or recombinantly produced interferons such as peginterferon alfa-2a.
Peginterferon alfa-2a (sold as Pegasys® by Genentech, South San Francisco, USA) is a covalent conjugate of recombinant alfa-2a interferon (having an approximate molecular weight of 20,000 daltons) with a single branched bis-monomethoxy polyethylene glycol (PEG) chain (having an approximate molecular weight of 40,000 daltons). The PEG moiety is linked at a single site to the interferon alfa moiety via a stable amide bond to lysine. Peginterferon alfa-2a has an approximate molecular weight of 60,000 daltons. The advantage of peginterferon alfa-2a over interferons that do not contain the PEG moiety is that peginterferon alfa-2a exhibits a longer half-life, requiring less frequent dosing.